The long-range goals of this project are to elucidate mechanisms involved in the CNS rewarding actions of ethanol, and the contribution of these rewarding effects toward maintaining high alcohol drinking. The overall hypothesis to be tested is that responsiveness of the limbic system to the reinforcing, stimulating effects of ethanol (EtOH) contributes toward the initiation of alcohol drinking and development of high alcohol drinking. The intra-cranial self-administration (ICSA) technique will be used to examine the reinforcing effects of EtOH and certain receptor agents within discrete regions. The micro-injection/micro-dialysis procedure will be use to assess the response of the meso-limbic dopamine (DA) system to the stimulating actions of EtOH and selected receptor agents. Aim 1 will test the hypothesis that the reinforcing effects of EtOH within the nucleus accumbens (ACB) shell are mediated by serotonin-3 (5-HT3), and/or 5-HT2A receptors. Aim will determine the involvement of the caudal ventral pallidum (VP) and/or the dorsal medial prefrontal cortex (mPFC) in mediating the reinforcing actions of EtOH. Aim 3 will examine neuronal mechanisms within the posterior ventral tegmental area (pVTA) that underlie the increased sensitivity and responsiveness of this region to the reinforcing effects of EtOH following chronic alcohol drinking. Aim 4 will test the hypothesis that alterations in the 5-HT3 receptor and D2 auto-receptor contribute to the development of sensitization to the stimulating effects of EtOH within the pVTA. To assess possible genetic influences on the rewarding, stimulating effects of EtOH within the limbic system, selected experiments will be conducted with alcohol-preferring (P) rats and stock Wistar rats. The results of this project will provide important information on (a) CNS sites and receptors mediating the reinforcing effects of EtOH, (b) neuronal mechanisms underlying the increased responsiveness of the pVTA to the stimulating, reinforcing effects of EtOH produced by chronic or repeated EtOH exposure, and (c) genetic influences on the reinforcing responses to EtOH. A better understanding of the complex basic brain mechanisms that contribute to high alcohol drinking behavior is critical for the development of treatment strategies for alcohol abuse. PUBLIC HEALTH RELEVANCE: Alcohol abuse and alcoholism present serious health, social and economic problems. In order to develop appropriate treatment strategies, it is important to understand the complex neuronal mechanisms that regulating the rewarding actions of alcohol that contribute to alcohol addiction. The objectives of this proposal are to determine neuronal mechanisms underlying the CNS reinforcing actions of alcohol that contribute to high alcohol drinking behavior.